The present invention is directed to magnetic resonance (MR) imaging and more particularly to such imaging using intermolecular double-quantum coherence (DQC) for soft tissue contrast in human subjects.
Intermolecular multiple quantum coherence (iMQC) among water spins is a physical phenomenon that possesses many interesting characteristics. The iMQC originates from dipolar interactions among spatially separated water nuclear spins, and the signal intensity from iMQC depends on, among other things, a correlation distance for the dipolar interactions which can be selected with experimental parameters. The potential use of this signal source to form MR images with novel contrast is tremendous, but very little work has been done in the past, due to a lack of sound understanding of factors affecting the formation, signal-to-noise ratio, and contrast of the images.
One particular form of iMQC is DQC, or double quantum coherence. DQC was mentioned briefly in W. S. Warren et al, xe2x80x9cGeneration of impossible cross-peaks between bulk water and biomolecules in solution NMR,xe2x80x9d Science 1993; 262:2005-2009. However, that article is primarily concerned with ZQC (zero-quantum coherence) and teaches that the correlation gradient eliminates all but the ZQCs.
Multiple spin echoes (MSEs) and intermolecular multiple-quantum coherences (MQCs) in highly polarized systems have generated tremendous interest but also controversy in the NMR community over the past few years. These phenomena have been described using either classical theory for the demagnetizing field or quantum-mechanical density matrix treatments. To date, both treatments have led to fully quantitative predictions of the signals for simple sequences, such as correlated 2D spectroscopy (COSY) or COSY Revamped by Asymmetric Z gradient Echo Detection (CRAZED) experiments. Warren et al have determined the connection between the demagnetizing field and intermolecular dipolar coupling. The residual dipolar couplings between distant spins are responsible for the dipolar demagnetizing field and give rise to the intermolecular MQCs. From the classical viewpoint, these phenomena are due to the demagnetizing field produced by the spatial modulation of the nuclear magnetization arising in the sample following the second pulse in the CRAZED sequence. Though there are still some theoretical issues which remain to be addressed, intermolecular dipolar interaction effects have lost much of their mystical character and are becoming useful tools in NMR. Recently there has been great interest in the potential of the MQC or MSE contrast mechanisms for MRI because these contrast mechanisms may provide improved detection of tumors and eliminate the need for contrast agent injection.
Warren and co-workers first proposed intermolecular zero-quantum coherence (ZQC) imaging which is insensitive to the magnetic field inhomogeneity and has a relatively higher signal-to-noise ratio (SNR) than other MQCs. They have obtained ZQC images with varying contrast which reveal structural features not seen in, conventional MR images. However, DQC imaging utilizing the prototype sequence 90xc2x0-t1-{gradient}-90xc2x0-{double-area gradient}-t2, was believed to be unable to result in meaningful signals from the DQCs with a long detection time t2 and a short evolution t1, which are the preferred conditions for imaging. Navon and co-workers used 1H double-quantum filtered (DQF) MRI to detect molecules associated with ordered structures, thus identifying a new type of contrast. That method, however, only detects signals from semi-solid constituents and is specific for imaging of connective tissues such as cartilage and tendons. Based on classical demagnetization field theory, van Zijl and co-workers attempted to form an image from the second spin echo, but found that the image had a very low SNR and no detectable contrast even at the high field strength of 4.7 T. Recently, Bifone and co-workers showed that MSE spectroscopic signals in a localized volume can be observed in vivo with a 1.5 T clinical MR scanner. However, the sensitivity of the detected signal was too low for MR Imaging. However, the experimental parameters for the acquisition of the signal from the DQCs were not optimized in these previous reports.
It is a primary object of the invention to develop an MRI imaging method based on MQC, and in particular on DQC. It is a further object of the invention to develop such an imaging method for soft tissue imaging in humans.
To achieve the above and other objects, the present invention is directed to a method of forming MR images using a source of signals that have previously been considered as either non-existent or too difficult to be detected. Theoretical analysis and computer numerical simulations have been used to characterize the behavior of spins undergoing multiple-quantum coherences (MQCs) and to design an optimal imaging acquisition scheme. The present invention permits double-quantum coherence (DQC) MR images in human brains. The invention also permits human brain multiple-quantum coherence images to be taken using a 1.5T NMR scanner. A theoretical analysis has been carried out, demonstrating how the signals from MQC should change as function of magnetic field strength, and has permitted the determination of the relative sensitivity of MQCs of different transition orders.
A combination of quantum and classical formalisms was used to describe the behavior of the evolution of nuclear spins, including the effects of relaxation and long-range dipolar interactions. Theoretical analysis was used to aid in the design of a DQC imaging sequence with conventional or echo planar imaging acquisitions on a 1.5T clinical scanner.
In spite of the relatively low sensitivity, DQC images of human brains have been obtained for the first time with acceptable signal-to-noise ratio on a whole-body 1.5 T scanner. The theoretical analysis suggests that signals from the intermolecular DQCs have sensitivity better than those from the zero-quantum coherence (ZQCs) for human brain imaging. Signals from non-DQCs were filtered out by selective magnetic field gradients, and signals from ZQCs were further suppressed through application of a two-step cycling of the gradients. Other experimental adjustments such as an adaptive receiver gain, longer TR, and increased acquisition windows were used to maximize the available signal. Images in phantoms and human brains demonstrate that the imaging sequence has excellent selection for the signal from DQCs. These images demonstrate contrast of various brain tissues different from conventional images. It reflects susceptibility variations over adjustable sub-voxel distances. When the pulse sequence was implemented with EPI acquisition, whole brain DQC images of reasonable signal-to-noise ratios can be obtained in less than a minute.
Acquisition of the human brain images based on DQCs in water was successfully achieved for the first time on a 1.5T clinical scanner. The DQC signal provides new contrast for the detection of varying microstructure in soft tissues, which may potentially improve detection of tumors, and supply a new imaging tool for human brain functional studies.
The theoretical analysis shows that the present methods using DQC provide higher sensitivity than what was presented previously by Warren et al using ZQC. This higher sensitivity persists at all imaging field strengths. Experiments confirm the conclusions.
A new methodology is provided for using the DQC to study tumor oxygenation, human brain functional activation, and molecular diffusion imaging.
Pulse sequences, acquisition schemes, and gradient waveforms allow most efficient acquisitions of iMQC signals, and specific quantitation of different parameters.
The present technique will have large impacts on the research and clinical applications in which MRI is used.
Specifically, there are several technical developments which distinguish the present invention over the work of Warren et al:
1. The present invention permits calculation of the relative sensitivity of DQC and ZQC signals and successful implementation of DQC images for humans.
2. The present invention incorporates several measures in the imaging pulse sequence design to achieve optimal sensitivity for iDQC signal detection: (a) The xcex2=xcfx80/2 pulse in the original CRAZED sequence was replaced with a xcfx80/3 pulse. The maximum signal derived from iDQCs is increased by a factor of 3{square root over (3)}/4. (b) The position of the acquisition window is adjusted, and a large acquisition window (small bandwidth) is used to sample a broad range of time-domain signals. (c) Receiver dynamic range is optimized. In the implementation of DQC imaging disclosed herein, the default coil configuration file for the GE quadrature head coil was modified to increase the reconstruction scale by 18 dB during acquisition of DQC images. (d). A two-step cycle scheme-of DQC-encode gradients was designed to remove other undesired coherence pathways. A pair of gradients of very small amplitude along the y-direction before phase-encode gradients is used to eliminate the residual contamination from coherences other than DQCs.
3. The present invention implements DQC imaging pulse sequences with the following options: (1) without any refocusing xcfx80 pulses during DQC evolution and detection periods (referred to as GRE-DQC); (2) with refocusing xcfx80 pulses during DQC detection period only (referred to as SE-DQC); (3) with refocusing xcfx80 pulses during both iDQC evolution and detection periods (referred to as 2xcfx80-DQC). Contrast in images depends on the use of these refocusing pulses in the evolution and detection periods. These properties of our pulse sequence design were tested with brain fMRI studies.
4. DQC pulse sequences have been designed to measure diffusion rates of DQC and proved the apparent diffusion coefficient of DQC to be twice as large as SQC diffusion coefficient. Using the DQC diffusion weighted imaging, sensitivity to molecular diffusion will be twice as much as the conventional SQC DW imaging using the same diffusion gradient parameters 5. The DQC imaging technique has the enhanced sensitivity to local magnetic susceptibility variations which may be more sensitive to changes in blood oxygenation related to human brain neuronal activation.
Based on the same principles as outlined above for the pulse sequences, different iMQC imaging sequences and acquisition strategies can be implemented, including EPI in 3D, combined gradient-echo and spin-echo, spiral scan, keyhole, and back-projections. Due to the different behaviors of iMQCs with k-space sampling strategies, acquisition window positions, receiver bandwidth, and multiple-echo acquisitions, optimization of these parameters can result in improvements in signal-to-noise ratios for iMQC imaging. New applications can be based on the favorable features of iMQCs, including their selectivity to dipolar interactions of adjustable spatial scales, their higher sensitivity to molecular diffusion, and their long lasting signals in time domain. The inventors have performed a series of preliminary works on intermolecular multiple-quantum coherence imaging, and have established some important basis and understanding for further development of this potentially very useful technique. A combination of quantum mechanical and classical formalisms is used to describe the behavior of the evolution of nuclear spins under long-range dipolar interactions, in the presence of relaxation and molecular diffusion. Theoretical analysis is used to aid in the design of DQC imaging sequences with conventional or echo planar imaging acquisitions. For the first time, DQC images have been obtained of human brains on a whole-body 1.5 T scanner. Some important results from those works are summarized below:
1. Characteristics of MQC signals with quantum mechanical and classical theories. Intermolecular dipolar effects in highly polarized spin systems such as water have been studied. Expressions for iMQCs under the influence of magnetic field gradients of varying magnitudes, directions, and durations were explicitly derived with the density matrix formalism and demagnetizing field theory. The time-averaged, not instantaneous, orientation of the applied gradients determines the contributions of long-range intermolecular dipole effects to multiple-quantum coherences. The time-averaged gradients served as a general model for gradients used for iMQC selection in imaging sequences. Theoretical and experimental results demonstrate, for the first time, that when the time-averaged orientation of a series of gradient pulses during the evolution period is at the magic angle, intermolecular dipolar effects are suppressed. The experimental evidence presented strongly supports the theoretical predictions and provides basis for coherence-select gradient designs for iMQC imaging.
2. With the apparent diffusion rates for MQC diffusion, Dnapp, defined as the slope of the MQC signal intensity vs. diffusion weighting gradients, the apparent diffusion rates of intermolecular MQCs are different from that of the intra-molecular MQCs; they follow the relationship: Dnapp=nDT, where DT is the translational molecular diffusion coefficient. These results coincide with neither Dnapp=n2DT for the ordinary MQC model nor Dnapp=DT for the simple classical demagnetizing model.
3. The inventors have designed pulse sequences which allow detection of signal decay solely depending on either iMQC relaxation or diffusion during the evolution period, and pulse sequences with selective excitation of specific nuclear spins interacting with different spins. These developments allow us to probe iMQCs during different time period to provide answers to some basic questions concerning MQC.
4. It is demonstrated that both the ZQC and DQC signal intensities increase with increased static field strengths. The advantage of DQC over ZQC in sensitivities, however, remains with increased field.
5. When signal intensity from a DQC image is measured as a function of echo time TE in human brains, a maximum in signal vs. TE appears when TE equals T2. There is a good agreement between the detected signal changes and the theoretical prediction for the GM and WM of the brain.
When the MQC signals are detected with varying xcfx84, the signal attenuation during this period depends on T*2,n, which is a sum of the contributions of the intermolecular MQC T2,n and the magnetic field inhomogeneities. An estimate of signal losses during the evolution and fitting to the theoretical curve to measured signal integrals can thus provide a measure of the MQC transverse relaxation time, T2,n or T*2,n.
We have implemented iDQC imaging pulse sequences at 1.5, 4 and 7 T with the following options: (1) without any refocusing xcfx80 pulses during iDQC evolution and detection periods (referred to as GRE-iDQC); (2) with refocusing xcfx80 pulses during iDQC detection period only (referred to as SE-iDQC); (3) with refocusing xcfx80 pulses during both iDQC evolution and detection periods (referred to as 2xcfx80-iDQC). Contrast in images depends on the use of these refocusing pulses in the evolution and detection periods.